NAP, an 8-amino-acid peptide (NAPVSIPQ, SEQ ID NO:1), is derived from activity-dependent neuroprotective protein, ADNP (U.S. Pat. No. 6,613,740; Bassan et al., J. Neurochem. 72: 1283-1293 (1999)). The NAP sequence within the ADNP gene is identical in rodents and humans (U.S. Pat. No. 6,613,740; Zamostiano, et al., J. Biol. Chem. 276:708-714 (2001)).
In cell cultures, NAP has been shown to have neuroprotective activity at femtomolar concentrations against a wide variety of toxins (Bassan et al., 1999; Offen et al., Brain Res. 854:257-262 (2000)). In animal models simulating parts of the Alzheimer's disease pathology, NAP was protective as well (Bassan et al., 1999; Gozes et al., J. Pharmacol. Exp. Ther. 293:1091-1098 (2000); see also U.S. Pat. No. 6,613,740). In normal aging rats, intranasal administration of NAP improved performance in the Morris water maze. (Gozes et al., J. Mol. Neurosci. 19:175-178 (2002)). Furthermore, NAP reduced infarct volume and motor function deficits after ischemic injury, by decreasing apoptosis (Leker et al., Stroke 33:1085-1092 (2002)) and reducing damage caused by closed head injury in mice by decreasing inflammation (Beni Adani et al., J. Pharmacol. Exp. Ther. 296:57-63 (2001); Romano et al., J. Mol. Neurosci. 18:37-45 (2002); Zaltzman et al., NeuroReport 14:481-484 (2003)). In a model of fetal alcohol syndrome, fetal death after intraperitoneal injection of alcohol was inhibited by NAP treatment (Spong et al., J. Pharmacol. Exp. Ther. 297:774-779 (2001); see also International PCT Application Publication No. WO 00/53217). Utilizing radiolabeled peptides these studies showed that NAP can cross the blood-brain barrier and can be detected in rodents' brains either after intranasal treatment (Gozes et al., 2000) or intravenous injection (Leker et al., 2002) or intraperitoneal administration (Spong et al., 2001).
SAL, a 9-amino acid peptide (SALLRSIPA, SEQ ID NO:19), also known as ADNF-9 or ADNF-1, was identified as the shortest active form of ADNF (see U.S. Pat. No. 6,174,862). SAL has been shown in in vitro assays and in vivo disease models to keep neurons of the central nervous system alive in response to various insults (e.g., Gozes et al., 2000; Brenneman et al., J. Pharmacol. Exp. Ther. 285:619-627 (1998)). D-SAL is an all D-amino acid derivative of SAL that is stable and orally available (Brenneman, et al., J Pharmacol Exp Ther. 309:1190-7 (2004)) and surprisingly exhibits similar biological activity (potency and efficacy) to SAL in the systems tested. ADNF-1 complexes are described in International PCT Application Publication No. WO03/022226.
Neuroactive peptides, such as NAP and SAL, appear to be extremely sensitive to even single-amino acid, conservative substitutions. See, e.g., Brenneman et al., J. Pharm. Ex. Ther., 285:619-627 (1998) and Wilkemeyer et al., Proc. Natl. Acad. Sci, USA, 100:8543-8 (2003). Thus, while NAP and SAL are model neuroactive peptides, even conservative peptide variations of their core sequences are not predicted to be therapeutically effective. Accordingly, while there have been advances in this field, there remains a need for further neuroactive peptides. The present invention solves this and other needs.